The p38 kinase is a mitogen-activated protein (MAP) kinase that belongs to the serine/threonine kinase superfamily. This kinase is activated by extracellular stresses such as heat, UV light, and osmotic stress, as well as by inflammatory stimuli such as lipopolysaccharide. When activated, p38 kinase phosphorylates intracellular protein substrates that regulate the biosynthesis of the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-β (IL-1β). These cytokines are implicated in the pathology of a number of chronic inflammatory disorders (Lee, et al., Ann. N.Y. Acad. Sci., 696, 149-170 (1993); Muller-Ladner, Curr. Opin. Rheumatol., 8, 210-220 (1996)), cardiovascular and central nervous system disorders (Salituro, et al., Current Medicinal Chemistry, 6, 807-823 (1999)), and autoimmune disorders (Pargellis, et al., Nature Structural Biology, 9(4), 268-272 (2002)).
A number of urea compounds (for example, WO 9923091, WO 01012188, WO 04004720, WO 04037789, WO 99/32111, US 2004/0058961, WO 2004/100946, and WO 0043384) have been identified as p38 kinase inhibitors or cytokine inhibitors. However, there remains a need for treatment in this field for compounds that are cytokine suppressive drugs, i.e., compounds that are capable of inhibiting p38 kinase.
The present invention provides new inhibitors of p38 kinase useful for the treatment of conditions resulting from excessive cytokine production.